Epithelial-to-mesenchymal transition (EMT) of carcinoma cells is thought to be at the basis of cancer invasion, and of the properties of carcinoma stem cells, and is therefore an important step in cancer progression. TGF-ss has been shown to induce EMT, and increased production of TGF-ss by cancer cells, resulting in increased autocrine TGF-ss signaling, is thought to initiate and drive cancer invasion and metastasis. TGF-ss signals through a heteromeric complex of transmembrane kinases that then activate Smads as transcription effectors that regulate gene expression, and several non-Smad pathways such as the Erk MAP kinase and PI3 kinase-Akt-TOR pathways. Whereas Smads regulate the gene expression program associated with EMT, the role of TGF-b-induced Erk MAP kinase signaling in EMT is unknown. Our lab recently showed that the type I TGF-ss receptor, TssRI, is a dual specificity kinase that becomes phosphorylated on Tyr in response to TGF-ss, and that TGF-ss induces the recruitment of ShcA to TssRI, resulting in ShcA phosphorylation by TssRI on Tyr and predominantly Ser. The recruitment and Tyr phosphorylation of ShcA by TssRI are required for TGF-ss-induced Erk MAP kinase signaling. I now propose a research project to further define the interaction of ShcA with TbRI in response to TGF-ss, and to evaluate the role of TGF-ss-induced ShcA recruitment and Erk MAP kinase signaling in TGF-ss-induced EMT and invasion. As part of this study I also aim to address the relative contributions of Tyr versus Ser phosphorylation of ShcA in TGF-ss-induced Erk MAP kinase signaling and EMT. Our results should lead to a better understanding of not only the mechanisms of TGF-ss signaling, but also the roles of TGF-ss signaling in EMT and cancer cell invasion. ) PUBLIC HEALTH RELEVANCE: Tumor invasion to other tissues is the primary cause of mortality in cancer patients. TGF-2, a protein that is secreted by tumor cells, signals the tumor cells to change in morphology and behavior, and allows them to invade and spread to other tissues. The proposed research aims to better understand the molecular pathways and signals that are activated when TGF-ss acts on cells, and their roles in cancer cell behavior, cancer progression and metastasis. This work may identify new targets for cancer therapy. )